Impact of Host NF-kB Signaling in Radiation Therapy
宿主 NF-kB 信号传导在放射治疗中的影响
基本信息
- 批准号:10434953
- 负责人:
- 金额:$ 36.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AnimalsAntitumor ResponseArginineAttenuatedCD8-Positive T-LymphocytesCancer PatientCell Surface ReceptorsCellsCessation of lifeChemicalsChronicClinicalClinical TrialsClonal ExpansionDNA BindingDNA DamageDataDefectDoseDrug usageFamilyGenerationsGenesImmuneInflammatory ResponseInvestigationIonizing radiationIrradiated tumorKnowledgeLeadLysineMediatingMemoryMolecularMusMutagensMutateNF-kappa BNuclearOxidative StressPathway interactionsPhase I Clinical TrialsPhase II Clinical TrialsPhysiologicalPost-Translational Protein ProcessingPublicationsRadiationRadiation therapyRegenerative capacityResearchRoleScheduleSignal PathwaySignal TransductionT cell responseT memory cellTestingTimeTranslationsTransplantationTreatment EfficacyTumor AntigensWild Type Mouseanti-PD-1basecancer cellcell killingcheckpoint therapyimprovedin vivoinhibitorinnovationirradiationmouse modelmutantneoplastic cellnovelnovel therapeuticspatient safetyresponsestem-like cellstemnesssuccesstranscription factortumortumorigenesis
项目摘要
PROJECT SUMMARY / ABSTRACT
Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface
receptors has significantly expanded the knowledge regarding the role of this transcription factor family in
regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA
damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed
study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining
anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically
modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that
radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells.
We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse
model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained
tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of
N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory
CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated
by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of
sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target
host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is
significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is
completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and
a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is
expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely
translation to clinical trials.
项目总结/摘要
不同细胞表面活性剂诱导的C→N NF-κB信号通路的研究
受体的研究极大地扩展了关于该转录因子家族在
调节免疫/炎症反应和肿瘤发生。相比之下,DNA的生理作用
损伤诱导的核-胞质(N→C)NF-κB信号转导仍然知之甚少。拟议
这项研究将通过阐明N→C NF-κB信号转导在维持NF-κB活性中令人惊讶的关键作用来填补这一知识空白。
体内放疗(RT)期间的抗肿瘤CD 8 T细胞反应。目前的建议利用基因
改良的小鼠模型,其在体内选择性地使N→C NF-κB信号传导失活。初步数据显示,
放射治疗可以以依赖于CD 8 T细胞的方式诱导同源肿瘤的持续消退。
我们还发现,一种特殊类型的记忆性CD 8 T细胞在肿瘤控制中被扩增,
模型最后,我们已经产生了一个令人鼓舞的数据与NF-κ B DNA结合抑制剂,以诱导持续的
放射治疗后肿瘤消退。基于这些观察,我们假设,
宿主N→C NF-κB信号通路通过产生肿瘤抗原特异性记忆促进放射治疗
CD 8 T细胞。我们将通过定义持续的肿瘤控制介导的细胞机制来验证这一假设。
通过抑制宿主N→C NF-κB信号通路(Aim 1),阐明放射治疗中NF-κB的分子机制,
在放射治疗中通过抑制宿主N→C NF-κB信号传导介导的持续肿瘤控制(Aim 2)和靶点
宿主N→C NF-κB信号传导与化学抑制剂,以改善放射治疗(目的3)。拟定研究
这是因为N→C NF-κB信号在调节宿主肿瘤反应中的生理作用是重要的,
完全不确定,这项研究将填补这一知识空白。它是创新的,因为一种新的小鼠模型,
将使用一种目前正在进行2期临床试验的新型化学抑制剂。最后,高影响是
这是因为上述抑制剂化学靶向N→C NF-κB信号传导可能会及时加速
转化为临床试验。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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SHIGEKI MIYAMOTO其他文献
SHIGEKI MIYAMOTO的其他文献
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{{ truncateString('SHIGEKI MIYAMOTO', 18)}}的其他基金
Impact of Host NF-kB Signaling in Radiation Therapy
宿主 NF-kB 信号传导在放射治疗中的影响
- 批准号:
10297956 - 财政年份:2021
- 资助金额:
$ 36.89万 - 项目类别:
Impact of Host NF-kB Signaling in Radiation Therapy
宿主 NF-kB 信号传导在放射治疗中的影响
- 批准号:
10665545 - 财政年份:2021
- 资助金额:
$ 36.89万 - 项目类别:
New Multi-Drug Resistance Mechanism in Multiple Myeloma
多发性骨髓瘤多重耐药新机制
- 批准号:
10439626 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
New Multi-Drug Resistance Mechanism in Multiple Myeloma
多发性骨髓瘤多重耐药新机制
- 批准号:
10626002 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
New Multi-Drug Resistance Mechanism in Multiple Myeloma
多发性骨髓瘤多重耐药新机制
- 批准号:
10029257 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
New Multi-Drug Resistance Mechanism in Multiple Myeloma
多发性骨髓瘤多重耐药新机制
- 批准号:
10187534 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
Regulation of NEMO modifications in radiation-induced NF-kB signaling
辐射诱导的 NF-kB 信号传导中 NEMO 修饰的调节
- 批准号:
8656285 - 财政年份:2013
- 资助金额:
$ 36.89万 - 项目类别:
Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers
小泛素样修饰剂对 NF-kappaB 的调节
- 批准号:
7986606 - 财政年份:2010
- 资助金额:
$ 36.89万 - 项目类别:
Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers
小泛素样修饰剂对 NF-kappaB 的调节
- 批准号:
8098970 - 财政年份:2010
- 资助金额:
$ 36.89万 - 项目类别:
Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers
小泛素样修饰剂对 NF-kappaB 的调节
- 批准号:
8505491 - 财政年份:2010
- 资助金额:
$ 36.89万 - 项目类别:
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